Since thienamycins were found in 1976 (JP-A 51-73191(1976), there have been made a number of researches and developments on carbapenem antibiotics.
Even today, studies are under way to synthesize a number of carbapenem compounds which have potent and broad antimicrobial spectra over Gram-negative bacteria and Gram-positive bacteria and are highly stable to many .beta.-lactamases.
For example, Taura et al. (JP-A 6-157544(1994)) have reported carbapenem compounds having a .beta.-configuration methyl group, a (6,7-dihydro-5H-pyrazolo[1,2-.alpha.] [1,2,4] triazolium-6-yl)] thio group and a 1-substituted-hydroxyethyl group respectively at the 1-, 2- and 6-positions of the carbapenem skeleton. In addition, a number of compounds have been reported by JP-A 6-1791(1994), JP-A 6-16671(1994), JP-A 5-339269(1993), etc.
JP-A 6-87858(1994) has disclosed carbapenem derivatives having an aminoalkylpyrrolidinylthio group at the 2-position of the carbapenem skeleton and being similar to the compounds of the present invention in structure. This patent generally indicates carbapenem compounds having a 2-substituted-pyrrolidin-4-ylthio group as the side chain at the 2-position of the carbapenem skeleton wherein the substituent is a branched alkylene group having a primary, secondary or tertiary amino group or an ammonio group at the terminus. However, it neither states in general nor suggests any compound which has a cyclic amine- or lactam-substituted hydroxymethyl group as the side chain of the pyrrolidinylthio group at the 2-position of the carbapenem skeleton.
Frequent use of penicillin and cephalosporin antibiotics having broad antimicrobial spectra has caused a social problem of the appearance of resistant bacteria, in particular, methicillin-resistant Staphylococcus aureus (MRSA) and resistant Pseudomonas aeruginosa. There has been known no drug efficacious against these resistant bacteria and thus it is urgently required to develop novel chemicals therefor.
As described above, carbapenem antibiotics have potent and broad antimicrobial spectra over Gram-negative and Gram-positive bacteria and are stable to .beta.-lactamases. Although these carbapenem antibiotics are efficacious against bacteria resistant to a number of penicillin and cephalosporin antibiotics, their antimicrobial activities on these resistant bacteria are not always sufficient. The carbapenem antibiotics are poor in chemical stability and, furthermore, very easily metabolized by dehydropeptidase-I (DHP-I) localized in the kidney, etc., and thus lose their antimicrobial activities within a short period of time in vivo. These properties make the compounds not necessarily useful as a drug.
In addition, there remain some problems regarding safety for the human body (for example, side effects on the central nervous system and nephrotoxicity due to decomposition products) and an increase in resistant bacteria caused by the frequent use of carbapenem antibiotics such as thienamycin and imipenem.
Although several carbapenem antibiotics are now employed in the treatment of infectious diseases, there has not been developed a carbapenem antibiotic which has an excellent antimicrobial effect and a broad antimicrobial spectrum and is satisfactory in stability in vivo, safety for the human body (i.e., avoiding any toxicity), etc.